H3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans

Delaney, Kamila; Strobino, Maude; Wenda, Joanna M.; Pankowski, Andrzej; Steiner, Florian

doi:10.1038/s41467-019-10404-9

Cited by 22 publications

(12 citation statements)

References 79 publications

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“…Thus, the H3.3K27M and H3.1K27M oncohistones have dramatically different effects on Polycomb-regulated domains. This quantitative effect appears to be a conserved property of H3K27M mutant histones, as replication-coupled H3.2K27M oncohistones are more potent inhibitors of H3K27 trimethylation than H3.3K27M oncohistones in C. elegans ( Delaney et al, 2019 ). We further genotyped these cell lines by targeted gene sequencing ( Kuo et al, 2020 ), and identified multiple genetic alterations ( Supplementary file 5 ), including biallelic deletions of the CDKN2A gene in the two H3.1K27M-bearing cell lines.…”

Section: Resultsmentioning

confidence: 99%

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Sarthy

Janssens

Henikoff

et al. 2020

eLife

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Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Sarthy

Janssens

Henikoff

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…Thus, the H3.3K27M and H3.1K27M oncohistones have dramatically different effects on Polycomb-regulated domains. This quantitative effect appears to be a conserved property of H3K27M mutant histones, as replication-coupled H3.2K27M oncohistones are more potent inhibitors of H3K27 trimethylation than H3.3K27M oncohistones in C. elegans (Delaney et al, 2019). We further genotyped these cell lines by targeted gene sequencing (Kuo et al , 2020), and identified multiple genetic alterations (Supplementary File 5), including biallelic deletions of the CDKN2A gene in the two H3.1K27M-bearing cell lines.…”

Section: Resultsmentioning

confidence: 99%

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Sarthy

Janssens

Henikoff

et al. 2020

Preprint

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Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown if the oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

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“…H3K27M showed a strong affinity for methyltransferase EZH2, the catalytic subunit of the PRC2, repressing H3K27me3 and thereby inhibiting PRC2’s enzymatic activity. Among histone H3, H3.3 is a major variant, and the K27M mutation in histone H3.3 (H3.3K27M) has been identified as a driver mutation for DIPGs [ 89 ]. The mutant cells showed decreased levels and altered distribution of H3K27 trimethylation (H3.3K27me3) via multiple mechanisms, including aberrant PRC2 interactions and hampered H3.3K27me3 spreading.…”

Section: Synthetic Lethality In Idh-mutated Tumorsmentioning

confidence: 99%

Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers

Yao

Liu

Yin

et al. 2021

J Exp Clin Cancer Res

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Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) gain a novel function for the conversion of α-ketoglutarate (α-KG) to oncometabolite R-2-hydroxyglutarate (R-2-HG). Two molecular entities namely enasidenib (AG-221) and ivosidenib (AG-120) targeting mIDH2 and mIDH1 respectively, have already been approved by FDA for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML). However, the low responses, drug-related adverse effects, and most significantly, the clinically-acquired resistance of AG-221 and AG-120 has shown great influence on their clinical application. Therefore, searching for novel therapeutic strategies to enhance tumor sensitivity, reduce drug-related side effects, and overcome drug resistance have opened a new research field for defeating IDH-mutated cancers. As the effective methods, synthetic lethal interactions and synergetic therapies are extensively investigated in recent years for the cure of different cancers. In this review, the molecules displaying synergetic effects with mIDH1/2 inhibitors, as well as the targets showing relevant synthetic lethal interactions with mIDH1/2 are described emphatically. On these foundations, we discuss the opportunities and challenges for translating these strategies into clinic to combat the defects of existing IDH inhibitors.

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H3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans

Cited by 22 publications

References 79 publications

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers

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